Opinion
Video
Therapeutic Strategies in gMG
Author(s):
An expert reviews targeted therapies in generalized myasthenia gravis, highlighting complement and neonatal Fc receptors.
James F. Howard Jr, MD: In 2013, the therapeutic strategies for myasthenia underwent a revolution, and for the first time we had an FDA-approved treatment for myasthenia. Believe it or not, a disease of several hundred years in age. We had no true therapy for MG [myasthenia gravis]. We borrowed everything from our transplant colleagues in terms of immune suppression. We now have targeted therapies that are approved by regulatory agencies throughout the world, and we have a number of them in the pipeline right now that will bear fruition this year and in the coming years. The 2 major classes of therapeutics that have been approved are ones that top that target complement and the other, the neonatal FC receptor. And these were designed based on what we knew about the pathophysiology of the disease. Myasthenia is unique. There are actually 3 pathophysiologic mechanisms of synaptic failure, first and foremost. And as we all know, and as we learned in our training, is that there is an antibody attack to the receptor complex of the neuromuscular junction, 95% to the actual receptor, about 8% to 10% is to muscle-specific kinase, 1% is to LRP (low-density lipoprotein receptor–related protein) 4. Then there’s a group for which we have no identifiable antibody as yet, or their antibodies are below the level of detection of our current assays. The second is…that antibody blocks the binding of neurotransmitter to the receptor complex. The antibody accelerates a normal turnover process of the receptor. Acetylcholine receptors turn over on an average of 7 to 10 days. Muscle-specific species…they’re internalized…degraded new receptors come to the surface, and the presence of antibody accelerates that, leading to a net loss of receptors on the surface of the membrane. And the third mechanism is a complement attack. Antibody binding to the receptor complex activates C1q, the complement cascade, ultimately leading to the formation of the membrane attack complex, and that architecturally destroys the neuromuscular junction. What we don’t know [is] which of these mechanisms is predominant at any given moment in time, in any given patient. And my personal belief is that there are those that are predominantly antibody dependent [and] those that are predominantly complement dependent. A whole bunch of them sit in the middle. And I even believe that it fluctuates or moves back and forth, depending upon a variety of circumstances that we’ve yet to define at this point in time. And this has impacted our treatment strategy. At this point without a biomarker, we can’t predict who will respond best to what form of therapy. And so, the game is on, if you will, to identify that. And we solicit any of the listeners to make a career in trying to identify a biomarker therapeutic effect in this disease. How we target the antibody has been through broad immune suppression. That’s now changing. We have targeted therapies by inhibiting the neonatal Fc receptor, which is a salvage pathway for immunoglobulin. IgG [immunoglobulin G] is internalized, bound FcRn [neonatal Fc receptor] and recirculated back to the vascular space. That’s what gives IgG and its associated antibodies a very prolonged half-life. And by inhibiting FcRn, we then shunt loose immunoglobulin antibody to the lysosome for destruction. We have other means of targeting the antibody through B-cell depletion. And those trials are in progress as we speak. We can target things like CD19, CD20. Rituximab targets CD20. CD19 has a broader expression on the B-cell repertoire and those trials are under way. We have no data in terms of efficacy. We can also target other aspects of the immune system that produce or [are] in the stream of producing antibody. One of which to look at is the plasma cells and using a very novel technique of CAR [chimeric antigen receptor] T[-cell] therapy. And we’re all familiar with CAR T in the oncologic space that ingrains the genetic code into the DNA that then targets a specific cell signal and destroys that cancer cell. Yet DNA CAR T is fraught with lots of [adverse] effects—cytokine release syndrome, the neurologic complications called ICANS [immune effector cell–associated neurotoxicity syndrome]. And those rates can be as high as 60% to 90%, depending upon the study that one reads. That’s not acceptable in a chronic autoimmune disorder. And so investigators are looking at RNA-based CAR T in which we do not ingrain this in perpetuity, and we will have to re-treat. But preliminary studies suggest efficacy with very few [adverse] effects and durability of response. That approach…may even exceed 1 year in time. Very early, very novel data. Too early to make any definitive conclusions at the time of this recording. But the hope is…this may prove to be an alternative approach as well. But none of that talks about the complement or deals with a complement aspect. This architectural destruction of the neuromuscular junction, first identified by Andrew [G.] Engel, [MD], at Mayo Clinic in the late [19]70s and therefore a class of drugs have come about that target complement [component] 5 that then inhibits the ability to form the membrane attack complex, what we now call the terminal complement complex. And in doing so, we have seen tremendous improvements in our patients. The currently available drugs are administered intravenously. We have one soon to be approved, hopefully, that will be subcutaneously administered, and other complement targets. Factor DC3, for instance, or even oral preparations. And so, with these new targeted therapies directly targeting, if you will, the mechanistic approach of disease, I think we’ve gained a tremendous jump forward in our ability to manage our patients. They work rapidly, unlike many of our drugs that take months to start working, and their [adverse] effect profiles are much better than the currently used drugs in our toolbox.
Transcript is AI-generated and edited for clarity and readability.
